EN
Project - A03:
The role of TNF in the regulation of hepatic autoimmunity
Project leaders:
Prof. Dr. rer. nat. Johannes Herkel &
Dr. rer. nat. Lorenz Adlung
Summary
Autoimmune hepatitis (AIH) is a chronic liver disease of unclear pathogenesis considered to be driven by autoreactive CD4+ T cells recognising hepatocellular autoantigens. Our aim is to elucidate the regulation of hepatic autoimmunity and the mechanisms behind the transition from preclinical autoimmunity to AIH. Our previous findings suggest an important role of TNF in AIH pathogenesis: intrahepatic CD4+ T cells in subjects with AIH are characterised by increased TNF production; hepatic TNF expression levels correlate with histological activity and fibrosis and, most importantly, we have obtained preliminary evidence in the “AIH-MAB” study that anti-TNF treatment is effective as a first-line steroid-free treatment in AIH. Therefore, we hypothesise that TNF-producing CD4+ T cells are key regulators of hepatic autoimmunity in AIH, promoting liver inflammation and damage by fuelling inflammatory mechanisms in the hepatic microenvironment. Our specific objectives are to elucidate the role of TNF in regulating hepatic autoimmunity by specifically investigating 1) the effects of TNF on the functions of regulatory and effector T cells, 2) the impact of TNF on the function of innate immune cells and 3) to identify the mechanisms that cause the upregulation of TNF in liver-infiltrating T cells in AIH. Using human samples from the AIH-MAB study, as well as samples from untreated individuals at initial diagnosis, and by using an antigen-driven mouse model of AIH that recapitulates the distinctive TNF production of autoreactive CD4+ T cells in the liver, we will perform single-cell transcriptome and interactome analyses combined with functional studies to address the role of TNF in autoimmune pathogenesis. We expect that our project will elucidate key aspects of autoimmune regulation in the liver and identify TNF-related genes and pathways as potential treatment targets for AIH.
Project plan
The aim of the project is to investigate the functional role of TNF in the regulation of hepatic autoimmunity and the transition of preclinical autoimmunity to autoimmune disease, using AIH as a paradigm. Our focus will be on the communication between TNF-producing T cells, other immune cells, including T cells and innate immune cells, and tissue cells. We expect that our project will significantly advance our understanding of hepatic immune regulation and autoimmune pathogenesis, and thus provide a basis for the development of improved treatments with better specificity, efficacy and tolerability.
Our hypothesis is that TNF produced by CD4+ T cells is a key factor in autoimmune pathogenesis that promotes and maintains liver inflammation and damage by fuelling inflammatory mechanisms in the hepatic microenvironment.
In this study, we will use samples taken from untreated people with AIH at first diagnosis and under anti-TNF treatment to perform single-cell analyses, interactome analyses and functional studies to address the role of TNF in AIH and the mechanisms of anti-TNF therapy. Deeper mechanistic studies that are not feasible in humans will be done using samples from a mouse model that recapitulates the distinctive TNF production of autoreactive CD4+ T cells in the inflamed liver. Therefore, we will combine our complementary personal experience and expertise in hepatic immune regulation (Herkel) and systems biology (Adlung) to address the following work packages:
WP1: To investigate the effects of TNF on adaptive immune cells in AIH.
WP2: To assess the impact of TNF-producing T cells on innate immune cells and parenchymal cells in AIH.
WP3: To identify mechanisms inducing TNF-production by liver-infiltrating T cells in AIH.
Project related publications
Herkel J, Carambia A, Lohse AW. Autoimmune hepatitis: Possible triggers, potential treatments. J Hepatol 2020;73:446-448. doi: 10.1016/j.jhep.2020.03.015. Open access.
Lüth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C, Brück W, Wraith DC, Herkel J#, Lohse AW#. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 2008;118:3403-10. doi: 10.1172/JCI32132.
Carambia A, Freund B, Schwinge D, Heine M, Laschtowitz A, Huber S, Wraith DC, Korn T, Schramm C, Lohse AW, Heeren J, Herkel J. TGF-β-dependent induction of CD4⁺CD25⁺Foxp3⁺ Tregs by liver sinusoidal endothelial cells. J Hepatol 2014;61:594-9. doi: 10.1016/j.jhep.2014.04.027. Open access.
Carambia A, Freund B, Schwinge D, Bruns OT, Salmen SC, Ittrich H, Reimer R, Heine M, Huber S, Waurisch C, Eychmüller A, Wraith DC, Korn T, Nielsen P, Weller H, Schramm C, Lüth S, Lohse AW, Heeren J, Herkel J. Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J Hepatol 2015;62:1349-56. doi: 10.1016/j.jhep.2015.01.006.Open access.
Krzikalla D, Laschtowitz A, Leypoldt L, Gottwick C, Averhoff P, Weidemann S, Lohse AW, Huber S, Schramm C, Schwinge D, Herkel J#, Carambia A#. IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in Mice. Cell Mol Gastroenterol Hepatol 2023;17:79-91. doi: 10.1016/j.jcmgh.2023.09.006.Open access.
Bovensiepen CS, Schakat M, Sebode M, Zenouzi R, Hartl J, Peiseler M, Li J, Henze L, Woestemeier A, Schramm C, Lohse AW, Herkel J, Weiler-Normann C. TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis. J Immunol 2019;203:3148-3156. doi: 10.4049/jimmunol.1900124. Open access.
Preti M, Schlott L, Lübbering D, Krzikalla D, Müller AL, Schuran FA, Poch T, Schakat M, Weidemann S, Lohse AW, Weiler-Normann C, Sebode M, Schwinge D, Schramm C, Carambia A#, Herkel J#. Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver. JCI Insight 2021;6:e141462. doi: 10.1172/jci.insight.141462. Open access.
Müller AL, Casar C, Preti M, Krzikalla D, Gottwick C, Averhoff P, Rosenstiel P, Gelderblom M, Altfeld M, Lohse AW, Steinmann S, Sebode M, Krause J, Schwinge D, Schramm C, Carambia A#, Herkel J#. Inflammatory type 2 conventional dendritic cells contribute to murine and human cholangitis. J Hepatol 2022;77:1532-1544. doi: 10.1016/j.jhep.2022.06.025. Open access.
Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, Baron U, Olek S, Wiegard C, Lohse AW, Weiler-Normann C, Schramm C, Herkel J. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol. 2012;57:125-32. doi: 10.1016/j.jhep.2012.02.029.
Oubounyt M, Adlung L, Patroni F, Wenke NK, Maier A, Hartung M, Baumbach J, Elkjaer ML. Inference of differential key regulatory networks and mechanistic drug repurposing candidates from scRNA-seq data with SCANet. Bioinformatics 2023;39:btad644. doi: 10.1093/bioinformatics/btad644.Open access.
# equal contribution